The present disclosure relates generally to compositions and methods for treating tumors. More particularly, the present disclosure relates to compositions including calcium carbonate nanoparticles and methods for neutralizing extracellular pH by administering the compositions of the present disclosure. Further disclosed are methods for treating cancers by administering the compositions of the present disclosure.
Cancer is now accepted as a disease caused by genomic instability and epigenetic factors. This understanding has ushered in a new set of drugs that target specific molecular pathways used by cancer cells to proliferate and elude the host defense system. Through genomic, proteomic, and metabolomics analyses, several highly successful molecularly targeted therapeutics have been developed such as Dasatinib, which targets tyrosine kinases (CML), and Temsirolimus, which targets mTOR (solid tumors such as renal cell carcinoma). While embodying the paradigm of most current therapeutic research, targeted therapeutics are rarely used for curative intent. Targeted therapeutics are also prone to selecting for resistant subclones, and most importantly, are often effective for only a small subset of clinical patients. Given an average development cost of about 1.8 billion dollars per drug, this inefficiency has clinicians turning towards alternatives, such as screening old drugs for off-label use. In addition, due to the redundancy of intracellular pathways, cells are able to mutate around the targeted pathway, developing resistance. Examples include Imatinib (Anti-BCR-ABL) and anti-Her-2 therapies, whose mechanisms of resistance are now active fields of study. Given the difficulties faced with molecularly targeted chemotherapeutics, these findings support the need to re-explore the hallmarks of cancer as a universal target for cancer therapy.
Malignant tumors rely on several fundamental pathophysiological processes for survival. Targeting these processes is the favored clinical approach because the agents can be widely used to treat diverse cancer types. Thus, most clinical progress involves therapeutics targeted against DNA replication, microtubules, and glycolysis. However, each of these methods has typically severe side-effects, including induced life-threatening immunodeficiency, peripheral neuropathy, and induced cachexia, respectively. Anti-mitotic agents, for example, have deleterious effects on any rapidly dividing normal cells, with life threatening implications from bone marrow loss that can lead to immunodeficiency and life threatening infection. With only a few exceptions, these chemotherapies are rarely curative and alternative compensatory metabolic pathways often lead to drug resistance. For example, glycolysis inhibitors are not effective because this conserved metabolic process is replaced by glutamine consumption from muscles, often leading to cachexia. In addition, any approach that targets intracellular pathways must outwit the upregulation of multidrug resistance (MDR) toxin efflux pumps by tumor cells and their intrinsic ability to mutate/modify these pathways seamlessly.
One unique hallmark of cancer is the acidic extracellular pH (“pHe”) found in a diverse range of tumors. Models on tumor pHe demonstrate a relationship between tumor invasiveness and the increased production of acid in most tumors. Increased acidity appears to be correlated to increased tumor invasiveness, with some hypotheses that tumor cells use this four-fold increase in hydrogen ion concentration to degrade the tumor matrix and sustain growth. To maintain normal intracellular pH (“pHi”) and to promote growth by degradation of the extracellular matrix, tumor cells actively transport the excess protons generated during enhanced glycolysis, the Warburg effect, to the extratumoral environment. This leads to a sustained acidic tumor environment, with an average extracellular pH of 6.8, as opposed to the buffered and highly regulated interstitial pH of about 7.4 in the vicinity of healthy tissue. Tumor cells actively use this 4 fold increase in hydrogen ion concentration to degrade the tumor matrix and thus sustain its growth.
The vaterite phase of calcium carbonate has biomedical significance due to its versatile properties including high dissolution, dispersivity, and biocompatibility. One of the most prevalent applications of calcium carbonate is as an antacid, which has been studied extensively in past. Calcium carbonate has three common polymorphs; calcite, vaterite and aragonite. Calcite is the most stable while vaterite is the least stable polymorph at room temperature and atmospheric pressure. The thermodynamic instability of the vaterite makes it convert to calcite over time under normal conditions. Due to this instability, the study of antacid properties of nanoscale vaterite phase calcium carbonate has not been completed. Much like other nanomaterials, CaCO3 has unique characteristics in comparison to its bulk counterpart including optical, mechanical, high surface area to volume size ratio, and surface chemical properties. Several attempts have been made to synthesize the meta-stable vaterite form of calcium carbonate, however these particles are either in the size range of a few microns, are not stable for an extended period of time, have low phase purity or require ultra-sonication and heating.
The acidic environment of cancer is a unique condition that can be targeted to treat diverse tumor types. Recently, groups have tried changing the low pH environment of tumors by either inhibiting carbonic anhydrases or directly neutralizing the tumor acid environment via systemic administration of oral sodium bicarbonate. Both of these models have shown efficacy in in vivo animal models. However, carbonic anhydrases are important in normal cell physiology and given the vast class of carbonic anhydrases available to tumors in their genetic material, whether the inhibitors can overcome the system's redundancy, such as that seen in anti-glycolytic drugs, remains unknown. The systemic administration of untargeted oral sodium bicarbonate to directly neutralize the acid environment of tumors is not practicable in clinics because of the potentially severe consequences of metabolic alkalosis. In addition, both of these treatments modify pH only temporarily. Accordingly, there exists a need for therapeutic approaches that primarily modify the extracellular environment and potentially avoid intracellular resistance mechanisms.